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WO1989004299A1 - Composes d'inhibition de lipoxygenase a base de furane et de pyrrole - Google Patents

Composes d'inhibition de lipoxygenase a base de furane et de pyrrole Download PDF

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WO1989004299A1
WO1989004299A1 PCT/US1988/004048 US8804048W WO8904299A1 WO 1989004299 A1 WO1989004299 A1 WO 1989004299A1 US 8804048 W US8804048 W US 8804048W WO 8904299 A1 WO8904299 A1 WO 8904299A1
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Prior art keywords
hydroxy
urea
ethyl
fur
alkyl
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James B. Summers
Bruce P. Gunn
Dee W. Brooks
James H. Holms
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Abbott Laboratories
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to organic compounds which inhibit lipoxygenase enzymes. It also relates to methods and compositions for inhibiting lipoxygenase enzymes in human and animal hosts in need of such treatment.
  • the lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid.
  • the enzyme 5-lipoxygenase converts arachidonic acid to 5- hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5- hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LTs) .
  • 12- and 15-lipoxygenase convert arachidonic acid to 12- and 15-HPET ⁇ , respectively.
  • Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
  • LTB4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovia! fluid of rheumatoid arthritic patients.
  • Leukotrienes have also been implicated as important mediators in allergic rhinitis, psoriasis, adult respiratory distress syndrome, Crohn's disease, inflammatory bowel disease, endotoxin shock, and ischemia induced myocardial injury among others.
  • the biological activity of the LTs has been reviewed by Lewis and Austen (J. Clinical Invest. 73, 889, 1984 and by J. Sirois (Adv. Lipid Res. 21, 78, 1985).
  • the product 12-HET ⁇ has been found in high levels in epidermal tissue of patients with psoriasis.
  • the lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils.
  • lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. Blocking these enzymes interrupts the biochemical pathways believed to be involved in these disease states.
  • R. is hydrogen, C, to C. alkyl, C 2 to C. alkenyl, or -NR 2 R 3 , wherein R 2 and R 3 are independently selected from hydrogen, C, to C. alkyl, hydroxyl, aryl or substituted aryl wherein substituents are selected from halo, nitro, cyano, C, to C 12 alkyl, alkoxy, halosubstituted alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and alkylsulfonyl; with the proviso that R 2 and 3 are not both hydroxyl;
  • X is oxygen, or NR.
  • R. is hydrogen, C, to C g alkyl, C, to C g alkoyl, arylalkyl or aroyl;
  • A is selected from C. to C- alkylene and C 2 to C g alkenylene; n is 0,1,2 or 3;
  • Y is selected independently at each occurrence from hydrogen, halogen, hydroxy, cyano, halosubstituted alkyl, C.. to C 12 alkyl, C 2 to C 12 alkenyl, C, to C 12 alkoxy, C 3 to C g ⁇ ycloalkyl, aryl, aryloxy, aroyl, C ⁇ to C 12 arylalkyl, C 2 to C ⁇ 2 arylalkenyl, C ⁇ to C 12 arylalkoxy, C ⁇ to C 12 arylthioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylalkylamino, arylalkylaminocarbonyl, alkoxyalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl, arylathioalkoxyalkyl and substituted derivatives of
  • the substituent(s.) Y can be substituted at any of the positions on the aromatic ring.
  • Examples of compounds which are themselves within the scope of the present invention include, but are not limited to, the following: N-hydroxy-N-(l-(5-methylfur-2-yl)ethyl) urea; N-hydroxy-N-(l-(5-phenylfur-2-yl)ethyl) urea; N-hydroxy-N-(l-(5-phenylfur-2-yl)ethy1)-N'-methyl urea; N-hydroxy-N-(l-(5-phenylfur-2-yl)ethyl) acetamide; N-hydroxy-N-(1-(5-(2-phenylethenyl)fur-2-y1)ethyl) urea; N-hydroxy-N-(l-(5-(2-phenylethenyl)fur-2-yl)ethyl) N'- methyl urea;
  • N-hydroxy-N-(l-fur-2-ylethyl) propionamide N-hydroxy-N-(1-(l-methyl-5-phenylpyrro1-2-yl)ethyl)-N'- methyl urea;
  • N-hydroxy-N-(3-fur-2-ylprop-2-enyl) urea N-hydroxy-N-fur-3-ylmethyl urea; N-hydroxy-N-(fur-3-ylmethyl)-N'-methyl urea; N-hydroxy-N-(5-(2, ,6-trimethylphenyl)-fur-2-ylethyl) urea; N-hydroxy-N-(l-(5-butylf r-2-yl)ethyl) urea;
  • N-hydroxy-N-(l-(5-methylfur-2-yl)ethyl)-N'-phenyl urea N-hydroxy-N-(l-(5-methylf r-2-yl)ethyl)-N'-(4-carboethoxy- phenyl) urea;
  • Preferred compounds of the invention include: N-hydroxy-N-(1-(5-methylfur-2-yl)ethyl) urea; N-hydroxy-N-(1-(5-phenylfur-2-yl)ethyl) urea; N-hydroxy-N-(l-(5-phenylfur-2-yl)ethyl)-N'-methyl urea; N-hydroxy-N-(l-(5-phenylfur-2-yl)ethyl) acetamide;
  • Most preferred compounds of the invention include:
  • N-hydroxy-N-(l-(5-benzyloxymethyIfur-2-yl)ethyl) urea N-hydroxy-N-(5-phenylfur-2-ylmethyl) urea; N-hydroxy-N-(3-fur-3-ylprop-2-enyl) urea N-hydroxy-N-(3-(5-phenylfur-2-y1)prop-2-enyl) urea; N-hydroxy-N-(1-fur-3-ylethyl) urea; N-hydroxy-N-(l-(5-pyrid-2-ylfur-2-yl)ethyl) urea; N-hydroxy-N-3-(l-(5-methylfur-2-yl)propenyl) urea; and N-hydroxy-N-((1-methyl)-3-(5-methylfur-2-yl)prop-2-enyl) urea.
  • alkylene is used herein to mean straight or branched chain spacer radicals such as -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 C(CH 3 ) 2 ⁇ , -CH 2 CH 2 CH 2 - and the like.
  • alkyl is used herein to mean straight or branched chain radicals of 1 to 12 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkenyl is used herein to mean straight or branched chain unsaturated radicals of 2 to 12 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
  • cycloalkyl is used herein to mean carbocyclic radicals, preferably of 3 to 8 carbons, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • alkoxy is used herein to mean -OR,- wherein R 15 i*s an alkyl radical, including, but not limited to methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
  • alkoyl is used herein to mean -COR.g wherein R. g is an alkyl radical, including, but not limited to formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, and the like.
  • alkoxycarbonyl is used herein to mean -C(0)R 17 wherein R.- is an alkoxy radical, including, but not limited to carbomethoxy, carboethoxy, carboisopropoxy, carbobutoxy, carbosec-butoxy, carboiso- butoxy, carbotert-butoxy, and the like.
  • aryl is used herein to mean substituted and unsubstituted aromatic carbocyclic radicals and substituted and unsubstituted heterocyclic aromatic radicals wherein the substituents are selected from halo, nitro, cyano, C, to C 12 alkyl, alkoxy, halosubstituted alkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and alkylsulfonyl including, but not limited to, phenyl, 1-naphthyl or 2-naphthyl, fluorenyl, pyridyl, quinolyl, thienyl, thiazolyl, pyri idyl, indolyl and the like.
  • heterocyclic aromatic refers to 5 and 6 membered aromatic rings having in the ring one, two or three heteroatoms selected from N, 0 and S; and also including benzo fused analogs of these 5 and 6 membered heterocyclic aromatic rings including, but not limited to, pyridyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl and the like.
  • aroyl is used herein to mean -C(0)R lg wherein R lg is an aryl radical, including, but not limited to benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.
  • aryloxy is used herein to mean -OR- g wherein R ⁇ g is an aryl radical, including, but not limited to phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • arylalkoxy is used herein to mean -OR 2Q wherein R 2Q is an arylalkyl radical, including, but not limited to phenylmethoxy (i.e., benzyloxy) , 4- fluorobenzyloxy, 1-phenylethoxy, 2-phenylethoxy, diphenylmethoxy, 1-naphthyl-methyloxy, 2-napthylmethyloxy, 9-fluorenoxy, 2-, 3- or 4-pyridylmethoxy, 2-, 3-, 4-, 5-, 6-, 7- , 8-quinolylmethoxy and the like.
  • phenylmethoxy i.e., benzyloxy
  • 4- fluorobenzyloxy 1-phenylethoxy, 2-phenylethoxy, diphenylmethoxy, 1-naphthyl-methyloxy, 2-napthylmethyloxy, 9-fluorenoxy, 2-, 3- or 4-pyridylmethoxy, 2-,
  • arylthioalkoxy is used herein to mean -S 21 wherein R 21 is an arylalkyl radical, including, but not limited to phenylthiomethoxy (i.e., thiobenzyloxy) , 4- fluorothiobenzyloxy, 1-phenylthioethoxy, 2-phenylthioethoxy, diphenylthiomethoxy, 1-naphthylthiomethoxy and the like.
  • arylalkyl is used herein to mean an aryl group appended to an alkyl radical, including, but not limited to phenylmethyl (benzyl), 1-phenylethyl, 2- phenylethyl, 1-naphthylethyl and the like.
  • arylalkenyl is used herein to mean an aryl group appended to an alkenyl radical, including, but not limited to phenylethenyl, 3-phenylprop-l-enyl, 3- phenylprop-2-enyl, 1-naphthylethenyl and the like.
  • halo and halogen are used herein to mean radicals derived from the elements fluorine, chlorine, bromine, or iodine.
  • halosubstituted alkyl refers to an alkyl radical as described above substituted with one or more halogens including, but not limited to, chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.
  • arylalkoxycarbonyl is used herein to refer to R 22 C(0)- wherein R 22 is an arylalkoxy group.
  • aminocarbonyl is used herein to ' refer to -C(0)NH 2 ⁇
  • alkylaminocarbonyl is used herein to refer to -C(0)NHR 23 wherein 23 is an alkyl group.
  • dialkylaminocarbonyl is used herein to refer to -C(0)NR_ 24.R2_5 c wherein R2_4. and R2D c are independently selected from alkyl.
  • arylalkylamino refers to R 2g NH- wherein R 2g is an arylalkyl group.
  • alkoxyalkoxyalkyl is used herein to refer to an alkoxy group appended to an alkoxy group which is itself appended to an alkyl radical including, but not limited to methoxyethoxymethyl, ethoxyethoxymethyl and the like.
  • alkoxyalkyl is used herein to refer to an alkoxy group appended to an alkyl radical including, but not limited to, methoxymethyl, ethoxymethyl and the like.
  • arylalkoxyalkyl is used herein to refer to an arylalkoxy group appended to an alkyl radical including, but not limited to, benzyloxymethyl, naphthylmethyloxymethyl and the like.
  • alkylsulfonyl refers to R 27 S0 2 - wherein R 2 _ is an alkyl group.
  • arylalkylaminocarbonyl is used herein to refer to R 28 C(0)- wherein 2g is an arylalkylamino group.
  • pharmaceutically acceptable cation refers to non-toxic cations including but not limited to cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethyl mmonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • lipoxygenase is used herein to mean 5- and/or 12-lipoxygenase.
  • the compounds of the invention inhibit lipoxygenase, which makes the compounds useful in the treatment and prevention of disease states wherein lipoxygenase may be involved, including, but not limited to, asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease and/or ischemia induced myocardial or brain injury.
  • lipoxygenase which makes the compounds useful in the treatment and prevention of disease states wherein lipoxygenase may be involved, including, but not limited to, asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease and/or ischemia induced myocardial or brain injury.
  • This invention also provides a method of treatment for inhibiting 5- and/or 12-lipoxygenase activity in a human or lower animal host in need of such treatment which method comprises administration to the human or lower animal host of a compound of the invention in a therapeutically effective amount to inhibit lipoxygenase activity in the host.
  • This invention also provides a method of treating asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, inflammatory bowel disease, endotoxin shock, and/or ischemia-induced myocardial injury in a human or lower animal in need of such treatment comprising administering to the human or lower animal a therapeutically effective amount of a compound described above. Further, this invention also provides a method of treating or preventing the symptoms of the disease states mentioned above.
  • the compounds of the present invention may be administered orally, parenterally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • parenteral as used herein includes subcutaneous, intravenous, intraarterial injection or infusion techniques, without limitation.
  • topically encompasses administration rectally and by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose.
  • Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and more usually 0.01 to 10 mg/kg/day.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
  • compositions in unit dosage form for the inhibition of 5- or 12-lipoxygenase activity in a human or lower animal host in need of such treatment comprising a compound of this invention and one or more nontoxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • the amount of active ingredient that may be combined with such materials to produce a single dosage form will vary depending upon various factors, as indicated above.
  • Injectable preparations such as oleaginous solutions, suspensions or emulsions, may be formulated according to known art, using suitable dispersing or wetting agents and suspending agents, as needed.
  • the sterile injectable preparation may employ a nontoxic parenterally acceptable diluent or solvent as, for example, sterile nonpyrogenic water or 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent as, for example, sterile nonpyrogenic water or 1,3-butanediol.
  • the other acceptable vehicles and solvents that may be employed are 5% dextrose injection, Ringer's injection and isotonic sodium chloride injection (as described in the USP/NF) .
  • sterile, fixed oils are conventionally employed as solvents or suspending media.
  • any bland fixed oil may be used, including synthetic mono-, di- or triglycerides.
  • Fatty acids such as oleic acid can also be used in the preparation of injectable compositions.
  • Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration include capsules, tablets, pills, troches, lozenges, powders and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, pharmaceutical adjuvant substances, e.g., stearate lubricating agents.
  • the dosage forms may also comprise buffering agents.
  • Solid oral preparations can also be prepared with enteric or other coatings which modulate release of the active ingredients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert nontoxic diluents commonly used in the art, such as water and alcohol. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying suspending, sweetening, flavoring and perfuming agents.
  • reagents can also be used to carry out the same transformation.
  • 2 can be converted to 3 using borane trimethyl amine, borane-tetrahydrofuran, or other borane complexes.
  • Intermediate 2 can also be converted to 3 with sodium cyanoborohydride or with phenyldimethylsilane in trifluoroacetic acid.
  • Hydroxylamine 3 can also be converted to 4 with acylating agents such as acetic anhydride in the presence of other bases such as pyridine.
  • Compounds of formula I wherein R., is -NR 2 R 3 can be prepared according to the method outlined in scheme 2, below.
  • Hydroxylamine 3 the synthesis of which was described above, is treated with gaseous HCl followed by phosgene.
  • the resulting putative carbamoyl chloride 6 is reacted without isolation with aqueous ammonia to yield the urea 7.
  • hydroxylamine 3 is treated with trimethylsilyl isocyanate (TMSNCO), followed by ammonium chloride workup to give the urea 7.
  • TMSNCO trimethylsilyl isocyanate
  • 3 can be treated with sodium or potassium cyanate in an acidic solution to yield the urea 7.
  • hydroxylamines such as 3 can be prepared as shown in scheme 4, below.
  • Chloride 8 is treated with Z-furfuraldehyde oxime and a base such as sodium methoxide to give nitrone 9.
  • the nitrone is then hydrolyzed under acidic conditions or with hydroxylamine.
  • the hydroxyl amine can be converted to compounds such as 5 and 7 using the methodology described above.
  • Compounds with other leaving groups such as bromides, iodides, tosylates, mesylates, triflates can be used instead of chloride 8.
  • Chloride 8 is heated with O-benzylhydroxylamine in a solvent such as dimethylsulfoxide or tetrahydrofuran to yield the new hydroxylamine 10.
  • This can either be reacted with acetyl chloride as in scheme 1 to yield 11 or with trimethylsilyl isocyanate as in scheme 3 to yield 12.
  • Compounds 11 and 10 are then hydrogenated to yield 5 and 7, respectively.
  • Other O-protected hydroxylamines can also be used in place of O-benzylhydroxylamine such as 0- tetrahydropyranyl hydroxylamine.
  • other methods can be used to convert 10 to 7, such as treatment with phosgene followed by ammonium hydroxide such as described in scheme 2, or treatment with sodium cyanate as described in scheme 3.
  • Furan 13 is first converted to 2-lithiofuran by treatment with n-butyllithium. This is then treated with the 0- benzyloxime of acetaldehyde in the presence of BF 3 3.Et 2 0 to give O-benzylhydroxylamine 10. This can be converted to the compounds such as 5 or 7 as described in scheme 4. Other O- protected oximes can be substituted for the O-benzyl oxime and other Lewis acids such as CeCl 3 can be used.
  • the following examples further illustrate the synthesis and use of compounds of this invention. The appropriate designations for R_, A, X and Y as defined by formula I are given for each example below.
  • the desired material was prepared according to the method of example 2, except using methyl isocyanate instead of trimethylsilyl isocyanate.
  • l-Methyl-2-phenyl pyrrole was prepared according to the method of example 2, step a, except using l-methylpyrrole instead of furan.
  • t-Butyl lithium (4.1 ml, 1.7 M in hexanes) was added to a solution of the pyrrole prepared as in step a, above (1.0 g, 6.4 mmole) in THF (25 L) at -78°C.
  • N-benzyloxy-N-(l-(l-methyl-5-phenylpyrrol- 2-yl)ethyl) N'-methyl urea was prepared using the method of example 1, step c, except using the material prepared as in part b, above instead of l-(5-methylfur-2-yl)ethyl hydroxylamine, and using methyl isocyanate instead of trimethylsilyl isocyanate.
  • d. N-hydroxy-N-(l-(l-methyl-5-phenylpyrrol-2- yl)ethyl) N'-methyl urea.
  • the material prepared as in part c, above was dissolved in methanol and palladium oxide on carbon (25 mg) added.
  • the desired compound was prepared according to the method of example 1, except using 3-furancarboxaldehyde instead of 2- acetyl-5-methyl furan and using methyl isocyanate instead of trimethylsilyl isocyanate.
  • the desired compound was prepared according to the method of example 2, except using mesityl bromide instead of bromobenzene and using methyl isocyanate instead of trimethylsilyl isocyanate.
  • the desired compound was prepared according to the method of example 2, steps b and c except using 2-butyl furan instead of 2-phenylfuran.
  • Examples 14-31 are prepared in a manner generally analogous to those described in examples 1-13 and schemes 1-6.
  • the solution was diluted with water (100 mL) and the pH adjusted to 8-9 by the addition of solid sodium carbonate.
  • the aqueous solution was extracted with ethyl acetate (3x100 mL) and the combined organic extract was washed with brine (1x150 mL) , dried over MgSO., filtered and concentrated to give an oil. Chromatography (silica gel, 60% ether in hexanes) gave the desired hydroxylamine intermediate (8.5 g) .
  • the desired material was prepared according to the method of Example 36, except using 5-methyl-2- furancarboxaldehyde instead of acetyl furan.
  • the desired material was prepared according to the method of Example 36, except using 5-methyl-2- furancarboxaldehyde instead of acetylfuran and methylisocyanate instead of trimethylsilyl-isocyanate.
  • the desired material was prepared according to the method of Example 39, except using ethyl 4- isocyanatobenzoate instead of phenyl isocyanate.
  • the product was chromatographed over silica gel with 60% ether/hexanes to yield a sticky white gum.
  • the intermediate, 2-acetyl-fur-5-yl N- benzylcarboxyamide was prepared according to the method of Example 45 except benzylamine was used instead of diethylamine in step a) .
  • the desired product was prepared according to the method of Example 43 starting at step c) using 2-acetyl-fur-5-yl N-benzylcarboxyamide instead of 2- acetyl-5-methoxycarbonylfuran.
  • the solid product was collected and washed with ether; m.p.
  • the title compound was prepared by the method of example 47, part a) using chloromethylbenzylether instead of 2-methoxy-ethoxymethylchloride.
  • the final product crystallized from ethyl acetate, was filtered and washed with ether, m.p.
  • the title compound was prepared by the method of example 36 using 3-acetyl-2,5-dimethylfuran instead 2- acetylfuran in an overall yield of 15%.
  • Example 74 ⁇ (pyrid-2-yl) 75 •(pyrid-3-yl) 76. •(pyrid-4-yl) 77 ⁇ (2-methylpyrid-3-yl) 78 ⁇ (5-methoxypyrid-3-y1) 79 ⁇ (N-methy1indo1-2-y1) 80 • (thiazol-2-yl) 81 •(pyrimid-2-y1) 82 • (4-methoxyphenyl) 83 • (4-chlorophenyl) 84 ⁇ (4-carbomethoxyphenyl) 85 •(4-cyanophenyl) 86 •(4-fluorophenyl)

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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés de furane et de pyrrole substitués utiles pour inhiber les enzymes de lipoxygénase, en particulier 5-lipoxygénase.
PCT/US1988/004048 1987-11-13 1988-11-14 Composes d'inhibition de lipoxygenase a base de furane et de pyrrole Ceased WO1989004299A1 (fr)

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KR1019890701315A KR970005906B1 (ko) 1987-11-13 1988-11-14 리폭시게나제 억제 화합물을 함유하는 푸란 및 피톨

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EP0404233A3 (fr) * 1989-06-23 1992-01-08 Norwich Eaton Pharmaceuticals, Inc. Emploi d'esters, amides et kétones de 5-phényl-2-furane comme agents neuroprotecteurs
EP0459748A3 (en) * 1990-06-01 1992-04-29 Lilly Industries Limited Thien-2-yl methylurea derivatives as leukotriene inhibitors
US5128364A (en) * 1991-03-28 1992-07-07 Merck Frosst Canada, Inc. Pyrrolo[1,2-a]indole hydroxylamine derivatives as inhibitors of leukotriene biosynthesis
US5132319A (en) * 1991-03-28 1992-07-21 Merck Frosst Canada, Inc. 1-(hydroxylaminoalkyl) indole derivatives as inhibitors of leukotriene biosynthesis
EP0525571A1 (fr) * 1991-07-31 1993-02-03 Bayer Ag Quinolin-2-yl-méthoxybenzylhydroxyurées comme inhibiteurs de la lipoxygénase
WO1995003292A1 (fr) * 1993-07-20 1995-02-02 Pfizer Inc. Heteroaryl cycloalcenyl hydroxiurees
US5612377A (en) * 1994-08-04 1997-03-18 Minnesota Mining And Manufacturing Company Method of inhibiting leukotriene biosynthesis
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5741809A (en) * 1992-08-24 1998-04-21 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders
US5750565A (en) * 1995-05-25 1998-05-12 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5780503A (en) * 1994-06-27 1998-07-14 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5856323A (en) * 1992-07-13 1999-01-05 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US6201016B1 (en) 1994-06-27 2001-03-13 Cytomed Incorporated Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6294574B1 (en) 1992-07-13 2001-09-25 Cytomed, Inc. Compounds and methods for the treatment of inflammatory and immune disorders
RU2404173C2 (ru) * 2008-10-07 2010-11-20 Институт нефтехимии и катализа РАН Способ получения метилового эфира 5-ацетилфуран-2-карбоновой кислоты

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IL95584A (en) * 1989-09-07 1995-03-15 Abbott Lab Indole-, benzoporene- and benzothiophene compounds including lipoxygenase-inhibiting compounds and pharmaceutical compounds containing them
US5476873A (en) * 1990-07-25 1995-12-19 Abbott Laboratories Acetylene derivatives having lipoxygenase inhibitory activity
DE69122759T2 (de) * 1990-07-25 1997-05-15 Abbott Lab Acetylenderivate mit lipoxygenase inhibitorischer wirkung
US5214204A (en) * 1991-07-19 1993-05-25 Abbott Laboratories Arylamidoalkyl-n-hydroxyurea compounds having lipoxygenase inhibitory activity
US5234933A (en) * 1991-10-31 1993-08-10 Board Of Governors Of Wayne State University And Vanderbilt University Cyclic hydroxamic acids
US5169854A (en) * 1992-02-26 1992-12-08 Abbott Laboratories N-substituted-furylalkenyl hydroxamic acid and N-hydroxyurea compounds having lipoxygenase inhibitory activity
US5639782A (en) * 1992-03-04 1997-06-17 Center For Innovative Technology Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors
JP2738486B2 (ja) * 1992-11-20 1998-04-08 ファイザー製薬株式会社 抗炎症剤としての新規なイソオキサゾリン類
US5292900A (en) * 1992-12-18 1994-03-08 Abbott Laboratories O-substituted N-hydroxyurea derivatives
US5506261A (en) * 1994-05-09 1996-04-09 Abbott Laboratories Substituted aryl- and heteroarylalkenyl-N-hydroxyurea inhibitors of leukotriene biosynthesis
US5516789A (en) * 1995-04-12 1996-05-14 Abbott Laboratories Lipoxygenase and cyclooxygenase inhibiting compounds
US5837719A (en) * 1995-08-10 1998-11-17 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
US5792778A (en) * 1995-08-10 1998-08-11 Merck & Co., Inc. 2-substituted aryl pyrroles, compositions containing such compounds and methods of use
US5908858A (en) 1996-04-05 1999-06-01 Sankyo Company, Limited 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
US5776954A (en) * 1996-10-30 1998-07-07 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
AU750592B2 (en) 1998-07-03 2002-07-25 Millennium Pharmaceuticals, Inc. Methods for synthesis of substituted tetrahydrofuran compound
CA2345919A1 (fr) 1998-07-03 2000-01-13 Gangavaram Vasantha Madhava Sharma Composes alicycliques d'oxygene substitues, procedes de synthese de ces composes
US6255498B1 (en) 1998-10-16 2001-07-03 Millennium Pharmaceuticals, Inc. Method for synthesizing diaryl-substituted heterocyclic compounds, including tetrahydrofurans
ID29027A (id) 1998-12-25 2001-07-26 Shionogi & Co Turunan-turunan heteroaromatik yang mempunyai aktivitas penghambatan terhadap integrase hiv
CN100406437C (zh) * 2002-01-11 2008-07-30 三共株式会社 氨基醇衍生物或膦酸衍生物以及含有它们的药物组合物
AU2005215320B2 (en) 2004-02-24 2008-04-17 Sankyo Company, Limited Amino alcohol compound
MX2010000465A (es) 2007-07-12 2010-08-30 Tragara Pharmaceuticals Inc Metodos y composiciones para el tratamiento de cancer, tumores y alteraciones relacionadas con tumores.
EP3563842A1 (fr) 2009-04-29 2019-11-06 Amarin Pharmaceuticals Ireland Limited Compositions pharmaceutiques comprenant de l'epa et un agent cardiovasculaire et leurs procédés d'utilisation
CA2926950C (fr) 2013-10-10 2022-10-11 Eastern Virginia Medical School Derives de 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide commeinhibiteurs puissants et selectifs de 12-lipoxygenase

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0404233A3 (fr) * 1989-06-23 1992-01-08 Norwich Eaton Pharmaceuticals, Inc. Emploi d'esters, amides et kétones de 5-phényl-2-furane comme agents neuroprotecteurs
EP0459748A3 (en) * 1990-06-01 1992-04-29 Lilly Industries Limited Thien-2-yl methylurea derivatives as leukotriene inhibitors
US5128364A (en) * 1991-03-28 1992-07-07 Merck Frosst Canada, Inc. Pyrrolo[1,2-a]indole hydroxylamine derivatives as inhibitors of leukotriene biosynthesis
US5132319A (en) * 1991-03-28 1992-07-21 Merck Frosst Canada, Inc. 1-(hydroxylaminoalkyl) indole derivatives as inhibitors of leukotriene biosynthesis
US5399698A (en) * 1991-07-31 1995-03-21 Bayer Aktiengesellschaft Quinolin-2-yl-methoxybenzylhydroxyureas
EP0525571A1 (fr) * 1991-07-31 1993-02-03 Bayer Ag Quinolin-2-yl-méthoxybenzylhydroxyurées comme inhibiteurs de la lipoxygénase
US5231103A (en) * 1991-07-31 1993-07-27 Bayer Aktiengesellschaft Quinolin-2-yl-methoxybenzylhydroxyureas
US5856323A (en) * 1992-07-13 1999-01-05 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US6294574B1 (en) 1992-07-13 2001-09-25 Cytomed, Inc. Compounds and methods for the treatment of inflammatory and immune disorders
US5741809A (en) * 1992-08-24 1998-04-21 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders
WO1995003292A1 (fr) * 1993-07-20 1995-02-02 Pfizer Inc. Heteroaryl cycloalcenyl hydroxiurees
US5665768A (en) * 1993-07-20 1997-09-09 Pfizer Inc. Heteroaryl cycloalkenyl hydroxyureas
US6420392B1 (en) 1994-01-06 2002-07-16 Millennium Pharmaceuticals, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5792776A (en) * 1994-06-27 1998-08-11 Cytomed, Inc., Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5780503A (en) * 1994-06-27 1998-07-14 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6201016B1 (en) 1994-06-27 2001-03-13 Cytomed Incorporated Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5612377A (en) * 1994-08-04 1997-03-18 Minnesota Mining And Manufacturing Company Method of inhibiting leukotriene biosynthesis
US6025384A (en) * 1995-05-25 2000-02-15 Leukosite, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5750565A (en) * 1995-05-25 1998-05-12 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6569895B1 (en) 1995-05-25 2003-05-27 Millennium Pharmaceuticals, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
RU2404173C2 (ru) * 2008-10-07 2010-11-20 Институт нефтехимии и катализа РАН Способ получения метилового эфира 5-ацетилфуран-2-карбоновой кислоты

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JPH03500887A (ja) 1991-02-28
KR890701557A (ko) 1989-12-20
EP0388429A1 (fr) 1990-09-26
AU614807B2 (en) 1991-09-12
US5112848A (en) 1992-05-12
EP0320628B1 (fr) 1997-01-15
CA1334975C (fr) 1995-03-28
DE3855757D1 (de) 1997-02-27
JP2545145B2 (ja) 1996-10-16
AU2803589A (en) 1989-06-01
KR970005906B1 (ko) 1997-04-22
EP0388429A4 (en) 1991-08-21
EP0320628A1 (fr) 1989-06-21

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